Ibuprofen is a non-competitive inhibitor of the peptide transporter hPEPT1 (SLC15A1): possible interactions between hPEPT1 substrates and ibuprofen

TY - JOUR

T1 - Ibuprofen is a non-competitive inhibitor of the peptide transporter hPEPT1 (SLC15A1): possible interactions between hPEPT1 substrates and ibuprofen

AU - Omkvist, Diana Højmark

AU - Larsen, Birger Brodin

AU - Nielsen, Carsten Uhd

PY - 2010/12

Y1 - 2010/12

N2 - BACKGROUND AND PURPOSE Recently, we identified etodolac as a possible ligand for the human intestinal proton-couple peptide transporter (hPEPT1). This raised the possibility that other non-steroidal anti-inflammatory drugs, and especially ibuprofen, could also interact with hPEPT1. Here, we have assessed the interactions of ibuprofen with hPEPT1.EXPERIMENTAL APPROACH The uptake of [ 14C]Gly-Sar, [ 3H]Ibuprofen and other radio-labelled compounds were investigated in Madin-Darby canine kidney cells (MDCK)/hPEPT1, MDCK/Mock, LLC-PK 1 or Caco-2 cells. The transepithelial transport of ibuprofen and hPEPT1 substrates was investigated in Caco-2 cell monolayers.KEY RESULTS Ibuprofen concentration dependently inhibited hPEPT1-mediated uptake of Gly-Sar in MDCK/hPEPT1 cells (K i app= 0.4 mM) but uptake of ibuprofen in Caco-2 cells and MDCK/hPEPT1 cells was not inhibited by hPEPT1 substrates. The maximum uptake rate for Gly-Sar uptake was reduced from 522 pmol.min -1.cm -2 to 181 pmol.min -1.cm -2 and 78 pmol.min -1.cm -2 in the presence of 0.5 mM and 1 mM ibuprofen, respectively. The interaction between ibuprofen and hPEPT1 was thus non-competitive. In LLC-PK1 cells, ibuprofen (1 mM) did not influence the transporter-mediated uptake of glycine or α-methyl-D-glycopyranoside. In Caco-2 cell monolayers the absorptive transport of δ-aminolevulinic acid was reduced by 23% and 48% by ibuprofen (1 and 10 mM), respectively. Likewise the transport of Gly-Sar was reduced by 23% in the presence of ibuprofen (1 mM).CONCLUSIONS AND IMPLICATIONS Ibuprofen is a non-competitive inhibitor of hPEPT1. As ibuprofen reduced the transepithelial transport of δ-aminolevulinic acid, drug-drug interactions between ibuprofen and hPEPT1 drug substrates at their site of absorption are possible if administered together.

AB - BACKGROUND AND PURPOSE Recently, we identified etodolac as a possible ligand for the human intestinal proton-couple peptide transporter (hPEPT1). This raised the possibility that other non-steroidal anti-inflammatory drugs, and especially ibuprofen, could also interact with hPEPT1. Here, we have assessed the interactions of ibuprofen with hPEPT1.EXPERIMENTAL APPROACH The uptake of [ 14C]Gly-Sar, [ 3H]Ibuprofen and other radio-labelled compounds were investigated in Madin-Darby canine kidney cells (MDCK)/hPEPT1, MDCK/Mock, LLC-PK 1 or Caco-2 cells. The transepithelial transport of ibuprofen and hPEPT1 substrates was investigated in Caco-2 cell monolayers.KEY RESULTS Ibuprofen concentration dependently inhibited hPEPT1-mediated uptake of Gly-Sar in MDCK/hPEPT1 cells (K i app= 0.4 mM) but uptake of ibuprofen in Caco-2 cells and MDCK/hPEPT1 cells was not inhibited by hPEPT1 substrates. The maximum uptake rate for Gly-Sar uptake was reduced from 522 pmol.min -1.cm -2 to 181 pmol.min -1.cm -2 and 78 pmol.min -1.cm -2 in the presence of 0.5 mM and 1 mM ibuprofen, respectively. The interaction between ibuprofen and hPEPT1 was thus non-competitive. In LLC-PK1 cells, ibuprofen (1 mM) did not influence the transporter-mediated uptake of glycine or α-methyl-D-glycopyranoside. In Caco-2 cell monolayers the absorptive transport of δ-aminolevulinic acid was reduced by 23% and 48% by ibuprofen (1 and 10 mM), respectively. Likewise the transport of Gly-Sar was reduced by 23% in the presence of ibuprofen (1 mM).CONCLUSIONS AND IMPLICATIONS Ibuprofen is a non-competitive inhibitor of hPEPT1. As ibuprofen reduced the transepithelial transport of δ-aminolevulinic acid, drug-drug interactions between ibuprofen and hPEPT1 drug substrates at their site of absorption are possible if administered together.

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1111j.1476-5381.2010.01000.x

DO - 10.1111j.1476-5381.2010.01000.x

M3 - Journal article

SN - 0007-1188

VL - 161

SP - 1793

EP - 1805

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

IS - 8

ER -